Protoflavone-chalcone hybrids exhibit enhanced antitumor action through modulating redox balance, depolarizing the mitochondrial membrane, and inhibiting ATR-dependent signaling

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dc.authoridEngin Ulukaya / 0000-0003-4875-5472en_US
dc.authoridElif Sedef Develi / 0000-0001-6696-7001
dc.authorscopusidEngin Ulukaya / 6602927353
dc.authorwosidEngin Ulukaya / K-5792-2018
dc.authorwosidElif Sedef Develi / GMD-9509-2022
dc.contributor.authorLatif, Ahmed Dhahir
dc.contributor.authorJernei, Tamas
dc.contributor.authorPodolski-Renic, Ana
dc.contributor.authorKuo, Ching-Ying
dc.contributor.authorVagvolgyi, Mate
dc.contributor.authorGirst, Gabor
dc.contributor.authorZupko, Istvan
dc.contributor.authorDeveli, Elif Sedef
dc.contributor.authorUlukaya, Engin
dc.contributor.authorWang, Hui-Chun
dc.contributor.authorPesic, Milica
dc.contributor.authorCsampai, Antal
dc.contributor.authorHunyadi, Attila
dc.date.accessioned2020-08-30T20:06:09Z
dc.date.available2020-08-30T20:06:09Z
dc.date.issued2020
dc.departmentİstinye Üniversitesi, Tıp Fakültesi, Temel Tıp Bilimleri Bölümüen_US
dc.description.abstractHybrid compounds combine fragments with complementary targets to achieve a common pharmacological goal. This approach represents an increasingly popular strategy for drug discovery. In this work, we aimed to design antitumor hybrid compounds based on an inhibitor of ataxia-telangiectasia and Rad3-related protein (ATR)-dependent signaling, protoapigenone, and a pro-oxidant ferrocene or chalcone fragment. Four new triazole-coupled hybrids were prepared. The compounds were cytotoxic against human breast cancer cell lines in vitro, showing IC(50)values in the sub-micromolar range. The nature of interactions between relevant fragments of the hybrids was evaluated by the Chou-Talalay method. Experimental combination treatment with the fragments showed additive effects or slight/moderate synergism, while strong synergism was observed when the fragments were virtually combined into their hybrids, suggesting a relevant pharmacological benefit of the coupling. All hybrids were strong inhibitors of the ATR-mediated activation of Chk1, and they interfered with the redox balance of the cells leading to mitochondrial membrane depolarization. Additionally, they induced late apoptosis and primary necrosis in MDA-MB-231 and MCF-7 breast cancer cells, respectively. Our results demonstrate that coupling the ATR-dependent signaling inhibitor protoflavone with a pro-oxidant chalcone dramatically increases the antitumor activity compared with either fragment alone. Such compounds may offer an attractive novel strategy for the treatment of various cancers.en_US
dc.description.sponsorshipNational Research, Development and Innovation Office, Hungary (NKFIH) [K-119770, K-129037]; Ministry of Human Capacities, Hungary [20391-3/2018/FEKUSTRAT]en_US
dc.description.sponsorshipThis work was supported by the National Research, Development and Innovation Office, Hungary (NKFIH; K-119770 and K-129037), and the Ministry of Human Capacities, Hungary grant 20391-3/2018/FEKUSTRAT.en_US
dc.identifier.citationLatif, A. D., Jernei, T., Podolski-Renic, A., Kuo, C.-Y., Vagvolgyi, M., Girst, G., … Hunyadi, A. (2020). Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling. ANTIOXIDANTS, 9(6). https://doi.org/10.3390/antiox9060519en_US
dc.identifier.doi10.3390/antiox9060519en_US
dc.identifier.issn2076-3921en_US
dc.identifier.issue6en_US
dc.identifier.pmid32545536en_US
dc.identifier.scopus2-s2.0-85086673123en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.3390/antiox9060519
dc.identifier.urihttps://hdl.handle.net/20.500.12713/394
dc.identifier.volume9en_US
dc.identifier.wosWOS:000551232600001en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.institutionauthorUlukaya, Enginen_US
dc.institutionauthorDeveli, Elif Sedefen_US
dc.language.isoenen_US
dc.publisherMdpien_US
dc.relation.ispartofAntioxidantsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectAntitumor Natural Producten_US
dc.subjectProtoflavoneen_US
dc.subjectChalconeen_US
dc.subjectFerroceneen_US
dc.subjectHybrid Compounden_US
dc.subjectFragment-Based Drug Designen_US
dc.subjectDna Damage Responseen_US
dc.subjectOxidative Stressen_US
dc.subjectVirtual Combination Studyen_US
dc.titleProtoflavone-chalcone hybrids exhibit enhanced antitumor action through modulating redox balance, depolarizing the mitochondrial membrane, and inhibiting ATR-dependent signalingen_US
dc.typeArticleen_US

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